Heterocyclylcarbonyl derivatives of urea

ABSTRACT

Heterocyclylcarbonyl derivatives of urea having the formula ##STR1## wherein R is a heterocyclyl group; and R 1  and R 2  when taken together with the nitrogen to which they are attached are morpholino, thiomorpholino or a 6-8 membered nitrogen containing heterocyclic ring; methods for their preparation and use as agents for dissolving gallstones.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of application Ser. No.7,722, filed Jan. 30, 1979, now abandoned, which in turn is a divisionalof application Ser. No. 884,858, filed Mar. 9, 1978, now U.S. Pat. No.4,163,784.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel heterocyclylcarbonyl derivatives ofurea, to processes for making them, and to their use as agents for thedissolution of gallstones, and in particular of cholesterol gallstones.

2. Description of the Prior Art

Cholelithiasis, one of the most common diseases of Western civilization,is under intensive investigation to determine not only thephysio-chemical changes in bile which lead to cholesterol gallstoneformation, but also how gallstones, once formed, can be dissolved. Anexcellent summary of the current state of such efforts is presented byBell in Gut, 15, 913-929 (1974).

Many attempts have been made to indirectly dissolve cholesterolgallstones by dietary manipulation or by oral administration of acompound so as to alter the composition of bile secreted by the liverand thus reverse the pathogenic process of cholelithiasis. Recently,prevention and even reversal of the pathogenic cholelithiasis process inman has been reported by the administration of chenodeoxycholic acid(U.S. Pat. Nos. 3,859,437 and 3,969,503, issued Jan. 7, 1975 and July13, 1976, respectively), a substance believed to inhibit synthesis ofcholesterol in the body.

Various acyl derivatives of urea have been described as useful agentsfor lowering blood cholesterol and for other purposes. U.S. Pat. No.4,014,876, issued Mar. 29, 1977, and Netherlands specification No.7016613, published May 14, 1971 disclose a series of1-(3-isoxazolylcarbonyl) ureas as hypoglycemic and/or blood free-fattyacid normalizing antidiabetic agents. French Pat. No. 2,120,032describes such compounds and methods for their preparation. Samejima,Yakugaku Zasshi, 80, 1706-12 (1960) (C.A. 55, 10439H, 1961) reportspreparation of several 1-(nicotinoyl) urea derivatives as intermediatesfor further synthesis. Guttman, et al., J. Pharm. Sci., 56(11) 1423-7(1967) describe 1,2-dihydro-1-methyl-2-oxoquinoxalinyl carbamyl urea, abase-catalyzed degradation product of 9-methylisoalloxazine.

U.S. Pat. No. 3,806,601, issued Apr. 23, 1974, describes the use ofbis(p-chlorophenoxy) acetylurea as a serum cholesterol and lipidlowering agent in adult animals suffering from hyperlipemia. However, adecrease in these levels by a given compound or compounds does notnecessarily imply that reversal of the pathogenic process ofcholelithiasis with indirect solubilization of cholesterol gallstoneswill occur. U.S. Pat. No. 3,245,878, issued Apr. 12, 1966, reports onseveral acyl (alkanoyl, aroyl)-3-benzyloxyureas as agents for loweringblood cholesterol.

South African Pat. No. 7,501,773, published Jan. 13, 1976, describes1-furoyl-3-(3-chloro-4-methylphenyl)-2-thiourea, a compound useful forcontrolling the ripening of sugar cane. SeveralN-carbamoylpyrazinecarboxamides useful as diuretics are described inU.S. Pat. No. 3,345,372, issued Oct. 3, 1967.

SUMMARY OF THE INVENTION

It has now been found that heterocyclylcarbonyl ureas having the formula##STR2## wherein R is selected from the group consisting of

pyridyl,

chlorosubstituted pyridyl,

quinolyl,

furyl,

3-(1,2,5-thiadiazolyl),

4-(1,2,3-thiadiazolyl),

3-(1,2-benzisothiazolyl) and

R₁ and R₂ when taken together with the nitrogen to which they areattached are selected from the group consisting of

morpholino,

thiomorpholino,

1-(1,2,3,6-tetrahydropyridyl),

1-azacycloheptyl,

1-azacyclooctyl,

3-(2,3,4,5-tetrahydro-3,1-benzazepinyl) and ##STR3## wherein Z isselected from the group consisting of hydrogen, alkyl having from one tofour carbon atoms, alkoxy having from one to four carbon atoms, chloroand phenylalkyl having from one to four carbon atoms in the alkyl group,

and the pharmaceutically acceptable acid addition salts of thosecompounds wherein R is a basic group are valuable agents for thedissolution of cholesterol gallstones in mammals, including humans.Additionally, they reduce biliary lipid pools in mammals.

Also included in this invention are the pharmaceutically acceptable acidaddition salts of those compounds wherein R is a basic group, e.g.pyridyl. Representative of such salts are the hydrochloride,hydrobromide, sulfate, phosphate, pamoate, citrate, malate, fumarate,tartrate, glycolate, maleate, p-toluenesulfonate, succinate, oxalate,mandelate, acetate and lactate. Such salts are prepared by knownprocedures.

The favored compounds of this invention are those wherein R₁ and R₂together with the nitrogen to which they are attached represent a6-membered ring. Preferred compounds are those favored compounds whereinNR₁ R₂ represents 1-(1,2,3,6-tetrahydropyridly) and R is pyridyl, chlorosubstituted pyridyl or 3-quinolyl.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are readily prepared by reaction of theappropriate heterocyclylcarbonyl isocyanate [R--CO--N═C═O] withdesirably an excess of an appropriate amine of formula HNR₁ R₂ in areaction-inert solvent at a temperature of from about 0° C. to about100° C. (Method A). The favored temperature range is from about 20° C.to about 50° C. since the reaction proceeds satisfactorily within thistemperature range as regards reaction rate and yield of product.Alternatively, they can be prepared by reacting the appropriateheterocyclylcarboxamides [R--CONH₂ ] with an appropriate isocyanate (R₂--N═C═O) under conditions similar to those described above. This latterprocedure, of course, affords products having only one substituent (R₂)on the terminal nitrogen of the desired product. Representative solventsfor these reactions are methylene chloride, ethylene dichloride,tetrahydrofruan, dioxane, diethyl ether, dimethyl ether of ethyleneglycol, benzene, toluene and xylene.

A further procedure comprises reacting the appropriate1-heterocyclyl-3,3-diphenylurea with an appropriate amine (HNR₁ R₂) in areaction-inert solvent at an elevated temperature in the presence of anacid (Method B). Temperatures of from about 50° C. to about 200° C. aresuitable for the reaction. The favored range is from about 85° C. toabout 150° C. Suitable solvents for this procedure are those enumeratedabove, the boiling points of which fall within the temperature rangecited.

The presence of an acid expedites the reaction. The acid can be addedseparately to the reaction mixture or can be added as an acid additionsalt of the amine reactant. The acid and amine are generally used inequimolar ratios. The ratio of acid to amine, however, is not criticalbut can vary from trace amounts of acid to up to several molar excesses.The favored ratio of acid to amine is from about 2:1 to about 1:2.

A still further procedure comprises acylation of a urea derivative ofthe formula H₂ N--CO--NR₁ R₂ with an appropriate heterocyclyl acidchloride R--COCl in a reaction-inert solvent, that is, a solvent whichdoes not react to any appreciable extent with the reactant or products.Suitable solvents include alkanols having from one to four carbon atoms,halogenated hydrocarbons such as methylene chloride, chloroform, carbontetrachloride, and hydrocarbons such as benzene, toluene, xylene,n-hexane, and cyclohexane. An acid acceptor is also used. Representativeacid acceptors for use in the above solvent systems are tertiary organicbases such as triethylamine, pyridine, collidine, picoline and alkalimetal alkoxides. Water can also be used as solvent since reaction occursprimarily and preferentially with the urea reactant. When using water assolvent, typical Schotten-Baumann reaction conditions are employed.Regardless of the solvent system used, the reaction is usually conductedat a temperature of from about 10° C. to about 100° C.

Another suitable procedure comprises reacting a lower alkyl ester of aheterocyclic carboxylic acid R--COOR° wherein R is as previously definedand R° is lower alkyl having up to four carbon atoms with the sodium (orpotassium) salt of an appropriate urea reactant of the formulaNaHN--CO--NR₁ R₂ in a reaction-inert solvent such as chloroform,N,N-dimethylformamide, toluene and tetrahydrofuran at a temperature offrom about -10° C. to about 70° C.

The requisite isocyanates of formula R--CO--N═C═O are convenientlyprepared by reaction of the corresponding amide with oxalyl chloride ina reaction-inert medium such as ethylene dichloride, xylene, toluene, attemperatures from about 0° C. to about 100° C. A slight excess, up to10%, of oxalkyl chloride is generally used to insure complete reactionof the amide. The isocyanate need not be isolated from the reactionmixture. In actual practice, it has been found most convenient to addthe amine reactant HNR₁ R₂ directly to the isocyanate containingreaction mixture.

When the isocyanate reactants are of the formula R₂ --N═C═O, they areprepared by reaction of the appropriate primary amine R₂ NH₂ withphosgene under reaction conditions similar to those described above.

The amide reactants used to prepare the isocyanate reactants describedabove are in turn prepared from the corresponding nitriles by hydrolysisaccording to known procedures. A convenient procedure comprises reactionof the nitrile with an alkali metal hydroxide, e.g., potassiumhydroxide, and hydrogen peroxide in a solvent such as ethanol attemperatures from about room temperature to the reflux temperature untilevolution of gas is complete. Alternatively, they are prepared byamidation of the corresponding acid chlorides according to well knownprocedures. The acid chlorides are prepared by reaction of theappropriate carboxylic acid with thionyl chloride, the latter generallyserving as reactant and solvent.

The compounds described herein are useful in dissolving gallstones inmammals and, when used for such purpose, are administered orally orparenterally in unit dosage form either alone or in the form ofpharmaceutical preparations; this is, in combination with othertherapeutic agents and/or a pharmaceutically acceptable carrier, thelatter selected on the basis of the chosen route of administration andstandard pharmaceutical practice. For example, they can be combined withvarious pharmaceutically-acceptable inert carriers in the form oftablets, capsules, lozenges, troches, hard candies, powders, aerosolsprays, aqueous suspensions or solutions, injectable solutions, elixirs,syrups and the like. Such carriers include solid diluents or fillers,sterile aqueous media and various non-toxic organic solvents. Moreover,the oral pharmaceutical compositions of this invention can be suitablysweetened and flavored by means of various agents of the type commonlyused for this purpose.

The particular carrier selected and the proportion of active ingredientto carrier are influenced by the solubility and chemical nature of thetherapeutic compounds, the chosen route of administration and the needsof standard pharmaceutical practice. For example, when the compounds ofthis invention are administered orally in tablet form, excipients suchas lactose, sodium citrate, calcium carbonate and dicalcium phosphatecan be used. Various disintegrants such as starch, alginic acids andcertain complex silicates, together with lubricating agents such asmagnesium stearate, sodium lauryl sulphate and talc, can also be used inproducing tablets for the oral administration of these compounds. Fororal administration in capsule form, lactose and high molecular weightpolyethylene glycols are among the preferred materials for use aspharmaceutically-acceptable carriers. Where aqueous suspensions are tobe used for oral administration, the compounds of this invention can becombined with emulsifying or suspending agents. Diluents such asethanol, propylene glycol, glycerine and chloroform and theircombinations can be employed as well as other materials.

For the purpose of parenteral administration, solutions or suspensionsof these compounds in sesame or peanut oil or in aqueous propyleneglycol solutions can be employed, as well as sterile aqueous solutionsof the soluble pharmaceutically-acceptable salts described herein. Theseparticular solutions are especially suited for intramuscular andsubcutaneous injection purposes should such method of administration bedesired. The aqueous solutions, including those of the salts dissolvedin pure distilled water, are also useful for intravenous injectionpurposes provided that their pH is properly adjusted beforehand. Suchsolutions should also be suitably buffered, if necessary, and the liquiddiluent first rendered isotonic with sufficient saline or glucose.

It is necessary that the active ingredient form a proportion of thecomposition such that a suitable dosage form will be obtained.Obviously, several dosage unit forms can be administered at about thesame time. Although compositions with less than 0.005% by weight ofactive ingredient might be used in certain instances, it is preferred touse compositions containing not less than 0.005% of the activeingredient; otherwise, the amount of carrier becomes excessively large.Activity increases with the concentration of the active ingredient. Thecomposition may contain 10, 50, 75, 95 or an even higher percentage byweight of the active ingredient.

The dosage unit administered can be any gallstone dissolving effectiveamount. Dosages of from about 10 mg./kg. to about 100 mm./kg. per day,and preferably from about 10 mg./kg. to about 50 mg./kg. per day areeffective in achieving the desired effect.

In addition to the above mentioned methods of administration, thecompounds of this invention can be administered by intraductal infusion,a method of considerable value in the treatment of patients havingstones retained in the common bile duct after cholecystectomy and commonduct exploration. It is of particular value in situations where thegallstones are between the T-tube and the duodenum. A convenient dosageform for this method is a saline solution buffered to pH 7.5.Concentrations of from about 10 millimoles to about 200 millimoles ofthe chose compounds are practical for such use. The solutions areallowed to drip into the duct at a rate of 30 ml. per hour for periodsof from 3 to 14 days.

The value of the herein-described compounds as agents for thedissolution of gallstones arises from their ability to decrease thelithogenic index; i.e., the relative concentrations of the three majorbile lipids: cholesterol, bile acids and phospholipids. It expresses thecholesterol level as a percentage of the concentration that would berequired to saturate bile of that particular bile acid and phospholipidconcentration or, it is 100 times the ratio of cholesterol actuallypresent to the maximal amount that would be soluble at thephospholipid-bile acid ratio of a given sample.

The effects of the compounds described herein, and their efficacy aredependent upon their increase in bile acid synthesis in vivo. Thecompounds increase the conversion of cholesterol to bile acids byincreasing the activity of the rate-controlling enzyme, cholesterol7α-hydroxylase. The direct measurement of bile acid synthesis in vivoand, hence, the determination of the ability of these compounds todissolve gallstones is accomplished according to the procedure ofSjovall, Meth. Biochem. Ana., 12, 123 (1964). In this procedure, malealbino mice, weight ca. 25 gm., are adapted to a synthetic diet(sucrose, casein, corn oil, salts and vitamins) for 1-2 weeks. They arethen fed the test compounds mixed into their diet (maximum 0.15%) for 4days. One day before sacrifice (3 days on drug), the mice are injectedi.p. with 0.2 ml. of solution containing (in 35 ml.) 10 μc 3H-cholicacid, 50 μc ¹⁴ C-cholesterol (both carrier free), 2% bovine serumalbumin, and 0.9% NaCl. Food consumption and initial and final bodyweights are recorded for each group. The animals are sacrificed 24 hoursafter injection by decapitation and exsanguination. The small intestineof each animal is removed and its contents rinsed into a screw-cap30-ml. polypropylene tube with 10 ml. saline. Saturated KOH (2.5 ml.)and carrier taurodeoxycholate are added to each tube, and the tubesautoclaved at 15 psi for 4 hours. The contents are acidified with 4 ml.conc. HCl and extracted with 2×15 ml. ethyl acetate. The extracts arecombined, dried over anhydrous granular sodium sulfate, and evaporatedunder nitrogen. The residue is treated with excess diazomethane inether-methanol, redried, and dissolved in a small volume of chloroform.Samples are streaked on silica gel GF thin layer chromatography plates(Analtech, 5 cm. lanes), developed in acetone-benzene (2:3), and stainedwith I₂ vapor. Two bands are located according to standards (C, cholate,and D, dihydroxy bile acids) and scraped into scintillation vialscontaining 1 ml. ethanol. Ten ml. of tritontoluene scintillation fluid(1:2, 40 gm. Omnifluor per liter) are added; radioactivity and externalstandard ratio are determined (Beckman LS-230, narrow ³ H and ¹⁴ Cchannels). Alternatively, C-band scrapings are mixed with 1.0 ml.iso-propanol and centrifuged; cholate is determined in duplicate 0.10ml. samples of supernatant; the remainder, including residual silicagel, is counted. Calculations are performed by PDP-10 computer program.Untreated controls are run dialy, and positive controls at frequentintervals (2% cholestyramine is run as standard). [Omnifluor is a blendof 98% 2,5-diphenyloxazole and 2% p-bis (o-methylstyryl)benzene,available from New England Nuclear Corp., Boston, Mass., U.S.A.].

Several of the compounds described herein, but by no means all, haveexhibited toxic effects when administered to animals at high doses. Forexample, oral administration of6-chloro-N-[1-(1,2,3,6-tetrahydropyridyl)carbonyl]nicotinamide to dogsat 250 mg./kg., ten times the projected efficacious dose, resulted indeath of the dogs, with pathological signs suggestive of cardiacimpairment. Administration of this agent at the same high dose to ratscaused only moderate toxicological symptoms, including lethargy,diminished appetite and weight gain, and slight abnormalities inclinical chemistry.

The compounds were tested for acute toxicity in the following manner.Healthy male CD-1 mice (20-25 g.), 10 mice per group, received a singlehigh dose of drug by intraperitoneal administration (1000 mg./kg., in0.6% Tween 20, at a concentration of 70 mg./ml.). (Tween 20,polyoxyethylene sorbitan monolaurate, available from Atlas ChemicalIndustries, Inc.). The animals were observed continuously for at leasttwo hours, again at 24 hours and daily thereafter for one week. Controlsreceived vehicle alone, 1.43 ml./kg. and were asymptomatic throughout.The compounds tested and the widely varying mortality rates observed aretabulated below.

    ______________________________________                                         ##STR4##                                                                                                  Mortality                                        R             NR.sub.1 R.sub.2                                                                             Rate                                             ______________________________________                                        6-chloro-3-pyridyl                                                                          1-(1,2,3,6-tetrahydro-                                                                       0/10                                                           pyridyl)                                                        3-pyridyl     1-(1,2,3,6-tetrahydro-                                                                       9/10                                                           pyridyl)                                                        ______________________________________                                    

In seven-day chronic toxicity tests on healthy male CD-1 mice, 5 miceper group, daily doses of 500 mg./kg. orally in 0.1% methyl cellulosefor 5 days,6-chloro-N-[1-(1,2,3,6-tetrahydropyridyl)carbonyl]nicotinamide producedhepatotoxicity. On the other hand,3-{N-[1,2-3,6-tetrahydropyridyl]carbonyl}-quinoline carboxamide showedno hepatotoxicity in the same test at the same high doses.

Despite the observation of toxicity of certain of the compounds of thisinvention at high dose levels in certain animal species; that is, atdose levels ten times the projected efficacious dose, said compounds areeffective and useful for dissolving cholesterol gallstones in mammals atdose levels substantially below those at which toxicity is observed.

EXAMPLE 16-Chloro-N-[1-(1,2,3,6-tetrahydropyridyl)-carbonyl]nicotinamide

To a solution of 6-chloronicotinamide (3.13 g., 0.020 mole) in dryethylene dichloride (75 ml.) under a nitrogen atmosphere is added oxalylchloride (2.86 g., 0.022 mole) and the resulting suspension stirred andheated at 85° C. for 90 minutes. The reaction mixture, now a clearsolution, is cooled to 20° C. Then, 1,2,3,-6-tetrahydropyridine (7.32g., 0.088 mole) is added dropwise, with stirring, at such a rate as tomaintain a temperature of 20°-30° C. Upon completion of addition, themixture is stirred an additional half hour at room temperature. Hexane(150 ml.) is added and the mixture extracted with 1 N sodium hydroxide(100 ml.) and then with water (100 ml.). The extracts are combined,filtered and acidified with acetic acid to pH 5.5. The crystallineproduct which precipitates is filtered, oven dried at 70° C. Yield 4.80g. (90.3%); m.p. 152°-154° C. Upon recrystallization from hot ethylacetate and drying the product melts at 158°-159.5° C. Yield 4.085 g.

Analysis: Calc'd. for C₁₂ H₁₂ O₂ N₃ Cl: C, 54.24; H, 4.55; N, 15.81%.Found: C, 54.30; H, 4.33; N, 16.12%.

EXAMPLE 2 N-(Hexamethyleneiminocarbonyl)isonicotinamide

A mixture of isonicotinamide (2.45 g., 0.02 mole), tetrahydrofuran (250ml.) and oxalyl chloride (2.08 ml., 0.024 mole) is refluxed under anitrogen atmosphere for 3.5 hours and is then cooled to roomtemperature. Hexamethyleneimine (9 ml., 0.08 mole) is added and thereaction stirred for one hour at room temperature. Benzene (200 ml.) isadded and the resulting mixture extracted with water (50 ml.). Theextract contains largely isonicotinamide. The reaction mixture isextracted with 1 N sodium hyroxide (50 ml.), the extract acidified withacetic acid and then extracted with ethyl acetate. Concentration of theethyl acetate extract affords 0.7 g. of oil which crystallizes fromethyl acetate-hexane (1:1). Yield 128 mg. (2.6%); m.p. 125°-127° C.

Analysis: Calc'd. for C₁₃ H₁₇ O₂ N₃ : C, 63.14; H, 6.93; N, 16.99%.Found: C, 63.03; H, 6.92; N, 17.07%.

EXAMPLE 3 N-(Piperidinocarbonyl)nicotinamide

To a mixture of nicotinamide (24.4 g., 0.20 mole) and dry ethylenedichloride (2500 ml.) is added oxyalyl chloride (38.1 g., 0.30 mole).The mixture is then heated to reflux for 4.5 hours and then cooled toroom temperature. It is filtered to give a clear pale orange solution ofnicotinyl isocyanate which is used directly in the next step.

Over a ten minute period a solution of diphenylamine (50.7 g., 0.30mole) in dry ethylene dichloride (100 ml.) is added to the isocyanatesolution. A precipitate forms immediately and the suspension is stirredat room temperature for an additional half hour. The reaction mixture isfiltered, the filter cake washed with ether and air dried. It isslurried in ether (2000 ml.), filtered and dried. Yield=39 g. m.p.141°-146° C. The dry crystals are dissolved in 1 N sodium hydroxide (350ml.), immediately filtered and the filtrate acidified with glacialacetic acid. The off-white precipitate ofN-(diphenylaminocarbonyl)nicotinamide is filtered and dried at 50° C.Yield=26.3 g. (42%); m.p. 142°-145° C.

A mixture of N-(diphenylaminocarbonyl)nicotinamide (1.6 g., 0.005 mole),toluene (50 ml.), piperidine (1.28 g., 0.015 mole) and glacial aceticacid (0.86 ml.) is heated and stirred at 95°-97° C. for one hour. Themixture is cooled to room temperature and extracted with 1 N sodiumhydroxide (50 ml.). The extract is acidified with glacial acetic acidand the oil which separates extracted with ethyl acetate. Evaporation ofthe extract under reduced pressure gives 1.9 g. of oil. The oil is takenup in ether (20 ml.), the solution made acid with ethyl acetate-HCl andthen diluted with an equal volume of hexane to precipitate a gum.Trituration of the gum with acetone (10 ml.) affords the crystallineproduct; m.p. 162°-164° C.

EXAMPLE 4

The following compounds are prepared from appropriate reactantsaccording to the procedures of Examples 1, 2 or 3. ##STR5##

    __________________________________________________________________________                                     Method of                                    R        NR.sub.1 R.sub.2  M.P.(° C.)                                                                   Example                                      __________________________________________________________________________    3-pyridyl                                                                              piperidino        162-164                                                                             1                                            3-pyridyl                                                                              4-methylpiperidino                                                                              105-108                                                                             1                                            3-pyridyl                                                                              4-(n-propyl)piperidino                                                                          121-123                                                                             1                                            3-pyridyl                                                                              4-(3-phenylpropyl)piperidino                                                                    93-96 1                                            3-pyridyl                                                                              4-chloropiperidino                                                                              118-120                                                                             1                                            3-pyridyl                                                                              4-benzylpiperidino                                                                              121-122                                                                             1                                            3-pyridyl                                                                              thiomorpholino    179-181                                                                             1                                            3-pyridyl                                                                              3-methylpiperidino                                                                              143-145                                                                             1                                            3-pyridyl                                                                              morpholino        165-166                                                                             1                                            3-pyridyl                                                                              1-azacycloheptyl  136-138                                                                             1                                            3-pyridyl                                                                              1-azacyclooctyl   93-96 1                                            3-pyridyl                                                                              3-(2,3,4,5-tetrahydro-3,1-benzazepinyl)                                                         155-157                                                                             1                                            3-pyridyl                                                                              1-(1,2,3,6-tetrahydropyridyl)                                                                   171-173.sup.(a)                                                                     3                                            4-pyridyl                                                                              piperidino        143-145                                                                             3                                            4-pyridyl                                                                              1-(1,2,3,6-tetrahydropyridyl)                                                                   117-119                                                                             1                                            4-pyridyl                                                                              1-azacycloheptyl  125-127                                                                             2                                            5-chloro-3-pyridyl                                                                     1-(1,2,3,6-tetrahydropyridyl)                                                                   133-135                                                                             1                                            6-chloro-3-pyridyl                                                                     piperidino        150-152                                                                             1                                            6-chloro-3-pyridyl                                                                     morpholino        144-146                                                                             1                                            6-chloro-3-pyridyl                                                                     3-methylpiperidino                                                                              115-116                                                                             1                                            6-chloro-3-pyridyl                                                                     thiomorpholino    143-145                                                                             1                                            6-chloro-3-pyridyl                                                                     4-(3-phenylpropyl)piperidino                                                                    138-140                                                                             1                                            6-chloro-3-pyridyl                                                                     2-methylpiperidino                                                                              143-145                                                                             1                                            6-chloro-3-pyridyl                                                                     1-azacycloheptyl  108-110                                                                             1                                            6-chloro-3-pyridyl                                                                     1-azacyclooctyl   117-119                                                                             1                                            6-chloro-3-pyridyl                                                                     4-chloropiperidino                                                                              157-159                                                                             1                                            6-chloro-3-pyridyl                                                                     4-(n-propyl)piperidino                                                                          130-132                                                                             1                                            6-chloro-3-pyridyl                                                                     H-benzylpiperidino                                                                              152-154                                                                             1                                            6-chloro-3-pyridyl                                                                     3-(2,3,4,5-tetrahydro-3,1-benzazepinyl)                                                         170-172                                                                             1                                            3-quinolyl                                                                             1-azacycloheptyl  146-148                                                                             1                                            3-quinolyl                                                                             4-benzylpiperidino                                                                              188-190                                                                             1                                            3-quinolyl                                                                             2-methylpiperidino                                                                              142-144                                                                             1                                            3-quinolyl                                                                             piperidino        152-154                                                                             2                                            3-quinolyl                                                                             1-(1,2,3,6-tetrahydropyridyl                                                                    157-159                                                                             2                                            5-quinolyl                                                                             piperidino        190-193                                                                             2                                            4-(1,2,3-thiadia-                                                                      piperidino        157-159                                                                             1                                            zolyl)                                                                        4-(1,2,3-thiadia-                                                                      1-(1,2,3,6-tetrahydropyridyl)                                                                   136-138                                                                             1                                            zolyl)                                                                        4-(1,2,5-thiadia-                                                                      piperidino        135-137                                                                             1                                            zolyl)                                                                        3-(benzisothia-                                                                        piperidino        116-118                                                                             1                                            zolyl)                                                                        3-(benzisothia-                                                                        1-(1,2,3,6-tetrahydropyridyl)                                                                   133-135                                                                             1                                            zolyl)                                                                        6-chloro-3-pyridyl                                                                     4-methylpiperidino                                                                              137-139                                                                             1                                            6-chloro-2-pyridyl                                                                     piperidino        155-156                                                                             1                                            2-furyl  piperidino        145-146                                                                             2                                            __________________________________________________________________________     .sup.(a) as hydrochloride                                                

EXAMPLE 5 Isonicotinoyl Urea

Urea (7.5 g., 0.125 mole) is suspended in liquid ammonia (250 ml.) in around bottom flask fitted with an acetone/dry-ice condenser. Sodiumpellets (2.9 g., 0.125 mole) are added and, after they have dissolved,methyl isonicotinate (12 g., 0.089 mole) is added to the mixture. Theammonia is allowed to evaporate from the mixture overnight. Theyellow-tan residue is dissolved in water (150 ml.), the pH of themixture adjusted to 5.5 with glacial acetic acid, and the precipitatewhich forms filtered, washed with water and air dried. It is then washedwith hexane and triturated with boiling methanol. The white solid(isonicotinic acid) is removed by filtration and the filtrate evaporatedto dryness to give the give the title product as a yellowish solid: m.p.245°-247° C. Quantitative analysis and infra-red data are consistentwith the values expected for the product.

EXAMPLE 6

The compounds tabulated below are prepared from appropriate reactants bythe procedures of Examples 1-3 or 5. ##STR6##

    ______________________________________                                                                       Method of                                      R           NR.sub.1 R.sub.2   Example                                        ______________________________________                                        3-pyridyl   4-methoxypiperidino                                                                              1                                              3-pyridyl   4-n-butoxypiperidino                                                                             1                                              3-pyridyl   3-chloropiperidino 1                                              4-pyridyl   morpholino         1                                              4-pyridyl   thiomorpholino     1                                              4-pyridyl   4-methylpiperidino 1                                              4-pyridyl   2-ethoxypiperidino 1                                              4-pyridyl   4-n-propylpiperidino                                                                             2                                              4-pyridyl   4-chloropiperidino 2                                              4-pyridyl   4-(3-phenylpropyl)piperidino                                                                     1                                              4-pyridyl   3-(2,3,4,5-tetrahydro-                                                                           1                                                          3,1-benzazepinyl)                                                 5-chloro-3-pyridyl                                                                        piperidino         3                                              5-chloro-3-pyridyl                                                                        2-chloropiperidino 3                                              5-chloro-3-pyridyl                                                                        4-ethylpiperidino  3                                              5-chloro-3-pyridyl                                                                        4-benzylpiperidino 1                                              5-chloro-3-pyridyl                                                                        4-ethoxypiperidino 1                                              5-chloro-3-pyridyl                                                                        morpholino         1                                              5-chloro-3-pyridyl                                                                        thiomorpholino     1                                              5-chloro-3-pyridyl                                                                        1-azacyclooctyl    2                                              2-chloro-3-pyridyl                                                                        4-(4-phenylbutyl)piperidino                                                                      1                                              2-chloro-3-pyridyl                                                                        1-azacycloheptyl   3                                              2-chloro-3-pyridyl                                                                        morpholino         3                                              2-chloro-3-pyridyl                                                                        4-n-butylpiperidino                                                                              3                                              2-chloro-3-pyridyl                                                                        2-methoxypiperidino                                                                              1                                              2-pyridyl   piperidino         2                                              2-pyridyl   3-ethylpiperidino  1                                              2-pyridyl   3-n-propoxypiperidino                                                                            1                                              2-pyridyl   thiomorpholino     2                                              2-pyridyl   2-chloropiperidino 1                                              2-pyridyl   4-benzylpiperidino 1                                              4-quinolyl  1-(1,2,3,6-tetrahydropyridyl)                                                                    1                                              5-quinolyl  1-(1,2,3,6-tetrahydropyridyl)                                                                    1                                              6-quinolyl  1-(1,2,3,6-tetrahydropyridyl)                                                                    1                                              7-quinolyl  1-(1,2,3,6-tetrahydropyridyl)                                                                    1                                              8-quinolyl  1-(1,2,3,6-tetrahydropyridyl)                                                                    1                                              2-furyl     1-(1,2,3,6-tetrahydropyridyl)                                                                    1                                              2-furyl     4-(3-phenylpropyl)piperidino                                                                     1                                              2-quinolyl  1-(1,2,3,6-tetrahydropyridyl)                                                                    1                                              3-(1,2,5-thiadiazolyl)                                                                    1-(1,2,3,6-tetrahydropyridyl)                                                                    1                                              3-(1,2,5-thiadiazolyl)                                                                    4-(n-butyl)piperidino                                                                            1                                              3-(1,2,5-thiadiazolyl)                                                                    4-(n-propoxy)piperidino                                                                          1                                              2-benzisothiazolyl                                                                        1-azacyclooctyl    1                                              3-benzisothiazolyl                                                                        morpholino         1                                              3-furyl     1-(1,2,3,6-tetrahydropyridyl)                                                                    1                                              3-furyl     piperidino         1                                              3-furyl     thiomorpholino     1                                              3-furyl     2-chloropiperidino 2                                              3-furyl     2-methylpiperidino 2                                              2-chloro-3-pyridyl                                                                        4-(4-chlorophenyl)piperidino                                                                     1                                              4-pyridyl   4-(4-chlorophenyl)piperidino                                                                     1                                              3-quinolyl  4-(2-chlorophenyl)piperidino                                                                     1                                              2-chloro-3-pyridyl                                                                        4-methoxypiperidino                                                                              1                                              2-pyridyl   1-(1,2,3,6-tetrahydropyridyl)                                                                    1                                              5-quinolyl  piperidino         1                                              6-quinolyl  1-azacyclooctyl    1                                              3-benzisothiazolyl                                                                        4-methylpiperidino 1                                              3-benzisothiazolyl                                                                        4-chloropiperidino 1                                              ______________________________________                                    

GENERAL METHODS FOR PREPARATION OF AMIDE REACTANTS

Method A

The appropriate acid reactant of formula R-COOH is heated to reflux inan excess of thionyl chloride for 3 hours. The reaction mixture is thenevaporated to dryness under reduced pressure and the residue added insmall portions with stirring to an excess of concentrated ammoniumhydroxide at room temperature. The mixture is stirred for one hourfollowing completion of addition and the product recovered by filtrationif it is insoluble or by evaporation of it is soluble.

Method B

The appropriate nitrile reactant of formula R-CN is added to ethanolcontaining a 10% excess of potassium hydroxide. To the resulting mixtureis added excess 30% hydrogen peroxide and the reaction mixture heatedgently to 60° C. The reaction becomes exothermic and is cooled ifnecessary to maintain the temperature at about 60° C. The reaction isallowed to continue until oxygen evolution ceases. It is thenconcentrated under reduced pressure to small volume, the residuefiltered, washed with water and dried.

I claim:
 1. A compound having the formula ##STR7## wherein R is selectedfrom the group consisting ofpyridyl chloro substituted pyridyl, and R₁and R₂ when taken together with the nitrogen to which they are attachedare selected from the group consisting of1-(1,2,3,6-tetrahydropyridyl),1-azacycloheptyl, 1-azacyclooctyl,3-(2,3,4,5-tetrahydro-3,1-benzazepinyl), and ##STR8## wherein Z isselected from the group consisting of hydrogen, alkyl having from one tofour carbon atoms, alkoxy having from one to four carbon atoms, chloroand phenylalkyl having from one to four carbon atoms in the alkyl group,and the pharmaceutically acceptable acid addition salts of thosecompounds wherein R is a basic group.
 2. A compound according to claim 1wherein R₁ and R₂ together with the nitrogen to which they are attachedrepresent 1-(1,2,3,6-tetrahydropyridyl).
 3. A compound according toclaim 2 wherein R is chloro substituted pyridyl.
 4. The compoundaccording to claim 3 wherein R is 5-chloro-3-pyridyl.
 5. A compoundaccording to claim 1 wherein R₁ and R₂ together with the nitrogen towhich they are attached represent ##STR9##
 6. A compound according toclaim 5 wherein Z is phenylalkyl.
 7. The compound according to claim 6wherein R is 2-chloro-3-pyridyl and Z is 4-benzyl.
 8. The compoundaccording to claim 6 wherein R is 6-chloro-3-pyridyl and Z is 4-chloro.